Multiple myeloma is the second most prevalent hematologic malignancy and accounts for over 10% of all hematologic cancers in the United States. It is estimated that over 16,500 new cases of myeloma are diagnosed and over 11,000 die from this disease each year. Although progress has been made in treatment over the last decade, the overall outlook for patients is grim. Multiple myeloma is a disease in which malignant plasma cells invade to populate and form tumors within the bone marrow. Their interactions with the tumor microenvironment lead to the release of cytokines that support myeloma cell proliferation, stimulate angiogenesis that supports myeloma cell growth and metastasis, and trigger bone lytic disease by over-stimulating differentiation of osteoclasts and their ensuing destruction of the bone. We have discovered a central mechanism in all of these processes that involves four effectors, each known to have a role in myeloma formation and progression - namely, the matrix receptor syndecan-1 (Sdc1), the av3 and av3 integrins, the insulin-like growth factor-1 receptor, and heparanase. The central mechanism is activation of a signaling complex comprised of Sdc1, the two integrins and the IGF1R when Sdc1 is activated by cleavage of its heparan sulfate chains by heparanase. Importantly, this mechanism is blocked by a peptide (called synstatin (SSTN)) that targets the active site on syndecan-1. This proposal will examine the mechanism by which Sdc1 is activated by heparanase on the myeloma cells, leading to tumorigenesis of the myeloma and heightened activation of vascular endothelial cells and osteoclast progenitors in the tumor microenvironment. Next, we will test the efficacy of SSTN as an inhibitor of this mechanism on the tumor cells and the cells in their microenvironment. The benefit of this work is likely to be new and effective treatments for multiple myeloma and other cancers.